Optical non-invasive blood monitoring system and method

ABSTRACT

A simple noninvasive technique that is capable of very accurate and fast blood analyte, e.g., glucose, level monitoring is provided. Fluctuation in the levels of glucose and other analytes affect the refractive index of blood and extra cellular fluid in biological tissue. Given that the propagation speed of light through a medium depends on its refractive index, continuous monitoring of analyte levels in tissue is achieved by measuring characteristics of the tissue that can be correlated to the refractive index of the tissue. For instance, the frequency or number of optical pulse circulations that are transmitted through an individual&#39;s tissue of known thickness within a certain time period can be correlated to an individual&#39;s blood glucose level.

REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part application of applicationSer. No. 11,492,451 which was filed on Jul. 25, 2006.

FIELD OF THE INVENTION

The present invention is directed to instruments and methods forperforming non-invasive measurements of analyte concentrations and formonitoring, analyzing and regulating tissue status, such as tissueglucose levels.

BACKGROUND OF THE INVENTION

Diabetes is a chronic life threatening disease for which there ispresently no cure. It is the fourth leading cause of death by disease inthe United States and over a hundred million people worldwide isestimated to be diabetic. Diabetes is a disease in which the body doesnot properly produce or respond to insulin. The high glucoseconcentrations that can result from this affliction can cause severedamage to vital organs, such as the heart, eyes and kidneys.

Type I diabetes (juvenile diabetes or insulin-dependent diabetesmellitus) is the most severe form of the disease, comprisingapproximately 10% of the diabetes cases in the United States. Type Idiabetics must receive daily injections of insulin in order to sustainlife. Type II diabetes, (adult onset diabetes or non-insulin dependentdiabetes mellitus) comprises the other 90% of the diabetes cases. TypeII diabetes is often manageable with dietary modifications and physicalexercise, but may still require treatment with insulin or othermedications. Because the management of glucose to near-normal levels canprevent the onset and the progression of complications of diabetes,persons afflicted with either form of the disease are instructed tomonitor their blood glucose concentration in order to assure that theappropriate level is achieved and maintained.

Traditional methods of monitoring the blood glucose concentration of anindividual require that a blood sample be taken daily. This invasivemethod can be painful, inconvenient, and expensive, pose the risk ofinfection and does not afford continuous monitoring. So-calledsemi-invasive (or less-invasive) methods require an individual to takesamples through the skin but the techniques do not puncture bloodvessels. Most semi-invasive glucose monitoring devices measure theconcentration of glucose that is present in the interstellar fluid thatis between the skin's surface and underlying blood vessels. The devicescould be implanted to provide continuous (real time) glucose levelmonitoring but individuals would have to undergo implantation surgery.Moreover, once implanted the devices are often inaccessible formaintenance.

Another glucose measuring method involves urine analysis, which, asidefrom being inconvenient, may not reflect the current status of thepatient's blood glucose because glucose appears in the urine only aftera significant period of elevated levels of blood glucose. An additionalinconvenience of these traditional methods is that they require testingsupplies such as collection receptacles, syringes, glucose measuringdevices and test kits. Although disposable supplies have been developed,they are costly and can require special methods for disposal.

Many attempts have been made to develop a painless, non-invasiveexternal device to monitor glucose concentrations. The variousapproaches have included electrochemical and spectroscopic technologies,such as near-infrared spectroscopy and Raman spectroscopy. These systemsmeasure blood glucose concentration based on IR blood absorption andemission at selected wavelengths. A major problem with thesenon-invasive optical techniques is that blood glucose absorption in thenear, mid or far IR regions is very weak. Compounding this problem isthe fact that water, proteins, fat, and other tissue components tend toblur the glucose fingerprint and thereby attenuate the detectablesignals and as a result these blood glucose monitoring devices are notvery accurate. Techniques used to compensate for the poor signals andthe related signal-to-noise problems including complicated spectralanalysis and processing instrumentation have not been successful. Thus,despite extensive efforts, none of these methods has, so far, yielded anon-invasive device or method for the in vivo measurement of glucosethat is sufficiently accurate, reliable, convenient and cost-effectivefor routine use.

SUMMARY OF THE INVENTION

The present invention is based in part on the recognition that glucoselevels affect the refractive index of blood and extra cellular fluid.Biological tissue is a very complex composition and, as used herein, thephrase “refractive index of tissue” refers to a composite or collectiverefractive index that is derived from the different refractive indicesof the various materials that are present in the tissue being monitored.Given that the propagation speed of light through a medium v depends onits refractive index n, as v=c/n, where c is the speed of light invacuum, it is possible to continuously monitor glucose levels in tissueby measuring characteristics of the tissue that can be correlated to therefractive index of the tissue and to the speed at which electromagneticradiation travels through the tissue.

For instance, with the present invention, the frequency or number ofoptical pulse circulations that are transmitted through tissue of knownthickness within a certain time period can be correlated to theindividual's blood glucose level. Thus, the invention provides a simpledesign that is capable of very accurate and fast blood glucose levelmonitoring.

In one aspect, the invention is directed to a device for noninvasivemeasurement of the levels of at least one analyte in a subject thatincludes:

means for irradiating the subject through tissue with electromagneticradiation;

means for detecting the radiation that passes through the tissue;

means for calculating the speed at which the electromagnetic radiationpasses through the tissue;

means for monitoring at least one of back or forward scattering ofelectromagnetic radiation within the tissue; and

means for correlating the calculated speed of the electromagneticradiation to the concentration of the at least one analyte in thesubject.

In another aspect, the invention is directed to a device for noninvasivemeasurement of the levels of at least one analyte in a subject thatincludes:

means for irradiating the subject through tissue with electromagneticradiation;

means for detecting the radiation that passes through the tissue;

means for calculating the speed at which the electromagnetic radiationpasses through the tissue; and

means for correlating the calculated speed of the electromagneticradiation to the concentration of the at least one analyte in thesubject, wherein the device defines a plurality of measuring channelsand wherein the plurality of measuring channels are operated by a singleelectronic processing unit.

The means for irradiating the subject through tissue withelectromagnetic radiation does not need to generate pulses at regularintervals.

In a further aspect, the invention is directed to a device fornoninvasive measurement of the levels of glucose in a subject thatincludes:

means for irradiating the subject through tissue with electromagneticradiation having a wavelength such that the speed of the electromagneticradiation propagating through the tissue is sensitive to the glucoseconcentration in the tissue;

means for detecting the radiation that passes through the tissue;

means for calculating the speed at which the electromagnetic radiationpasses through the tissue;

means for monitoring at least one of back or forward scattering ofelectromagnetic radiation within the tissue; and

means for correlating the calculated speed of the electromagneticradiation to the concentration of glucose in the subject.

In a yet another aspect, the invention is directed to a noninvasivemethod of monitoring the levels of at least one analyte in a subjectthat includes the steps of:

(a) irradiating the subject through tissue of known thickness withelectromagnetic radiation;

(b) detecting the radiation that passes through the tissue;

(c) calculating the speed at which the electromagnetic radiation passedthrough the tissue; and

(d) correlating the calculated speed of the electromagnetic radiation tothe concentration of the at least one analyte (e.g., glucose) in thesubject.

While the invention will be illustrated with glucose, it is understoodthat the invention provides the ability to achieve continuous monitoringand control of other blood constituents or analytes such as, forexample, cholesterol, triglycerides, urea, amino acids, and proteins,e.g., albumin and enzymes.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1, 4, and 5 are schematics of alternative configurations ofnon-invasive glucose level monitoring instruments;

FIG. 2 is a graph showing the change in pulse circulation frequency vs.glucose concentration measured with a glucose monitoring device usingradiation source with a wavelength of 850 nm;

FIG. 3 is a graph showing the sensitivity of a glucose monitoring devicevs. electronic processing unit (EPU) time delay;

FIGS. 6-13 are schematics of alternative configurations of non-invasiveglucose level monitoring instruments that employ a single electronicprocessing unit;

FIG. 14 is a cross-sectional view of a glucose monitoring device whenworn on the wrist of an individual;

FIG. 15 depicts the glucose monitoring device with the display panel;

FIG. 16 depicts the glucose monitoring device as worn on the wrist.

FIG. 17 illustrates the operation of the glucose monitoring devicetransmitting data and regulating an insulin pump; and

FIGS. 18A and 18B depict an ear-worn glucose monitoring device.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

As shown in FIG. 1, the glucose monitoring device includes an optical orlight source of electromagnetic radiation 1 and detector 2 which, areconnected to an electronic processing unit (EPU) 3. EPU 3, whichincludes a pulse generator 5, amplifier 6, counter 7 and timer 8, iscapable of generating, amplifying and counting electronic pulses andmonitoring time precisely. Source 1 and detector 2 are preferablydisposed on opposite sides of glucose-containing tissue 4, which is tobe monitored.

Optical source 1 can comprise any suitable conventional source such as,for sample, a laser, a laser diode, a light emitting diode (LED), orsome other type of light emitting device that is capable of generatinglight in a relatively narrow wavelength band in a high frequency pulseregime. The intensity should be sufficient to transmit through tissuebeing monitored but the intensity and energy levels of the radiationmust not be hazardous to the tissue. The radiation is preferably withinthe ultra-violet (UV), visible, infrared radiation (IR), and radiofrequency (RF) ranges. The light source 1 could also comprise abroadband light source such as a white light LED. Such a broadband lightsource can also be paired with one or more optical filters that aredesigned to pass only specific wavelength bands of light. Light source 1can also include appropriate optics that collimates and directs a beamof radiation into tissue 4.

Detector 2 can comprise a photodetector or any other type of devicecapable of high speed sensing the light that is transmitted throughtissue 4. The detector 2 could be configured to sense the intensity ofone or more particular wavelength bands. Suitable optics can be employedto collect and focus the transmitted radiation into the detector. TheEPU can be built using separate components or it can design as anintegrated microchip that supports several measurement channels.

For testing purposes, the glucose monitoring device can be calibrated byusing an aqueous solution that contains the appropriate amounts ofglucose, salts, proteins and other ingredients that are sufficient tosimulate the tissue that would be monitored.

In operation, tissue 4 is positioned between source 1 and detector 2 ofthe glucose monitoring device such that the thickness of the tissuethrough which radiation passes remains relatively constant during themonitoring process. Once tissue 4 is secured, the device is activated sothat pulse generator 5 produces an initial single electrical pulse tooptical source 1, in addition, pulse generator 5 simultaneously signalstimer 8 to begin its timing mechanism. Upon receiving the singleelectrical pulse, optical source 1 generates an optical pulse, whichpropagates through the monitored tissue 4. When the optical pulsereaches detector 2, the detector generates an electrical pulse toamplifier 6 which in turn commands counter 7 to register a pulsecirculation and signals pulse generator 5 to generate another singleelectrical pulse. Thereupon, pulse generator 5 immediately generates asecond single pulse to optical source 1 and the process of registeringthe circulating pulses is repeated. At the lapsed of a pre-selected andinstalled time duration, timer 8 sends a signal to counter 7 to recordthe number of pulse circulations that were registered during thepreceding time interval. In the meantime, pulse generator 5 continues togenerate a second set of pulses for a new measurement sequence. Asfurther described herein, for this glucose monitoring device whichoperates in the pulse circulation frequency measurement mode (alsoreferred to as pulse measurement mode), the number of pulses registeredwithin a prescribed time frame is proportional to the glucoseconcentration in the tissue and by gauging the changes in this pulsecirculation frequency, fluctuations in the individual's glucoseconcentration can be measured. With the inventive technique, it ispossible to circulate and detect a large number of pulse propagationsthrough the tissue even in a relatively short period of time, with eachmonitored pulse contributing to the final glucose concentrationmeasurement. The precision and high sensitivity exhibited by theinvention are attributable, in part, to the fact that the large numberof readings minimize the adverse effects that are contributed byaberrations and fluctuations caused by noise and other extraneousfactors.

The relationship between the number N of pulse circulations measuredwithin a time period t is expressed as follows:

$\begin{matrix}{{N = {\frac{t}{\frac{L\; n}{c} + {\Delta \; \tau}} = \frac{t}{\frac{L}{v} + {\Delta \; \tau}}}};} & (1)\end{matrix}$

where L is the thickness of the monitored tissue, n is the tissue'srefractive index, c is the speed of light in vacuum, v=c/n is thepropagation speed of the pulse in the tissue, and Δτ is the time delayin the EPU. (See, A. V. Loginov et al., “Fiber optic devices of datacollecting and processing,” Novosibirsk, “Nauka,” Siberian Branch,1991.) Similarly, the dependence of the tissue refractive index n=n (λ,C) on the wavelength λ and glucose concentration C in the tissue can bepresented as:

n(λ, C)=n₀(λ)+k(λ)*C;   (2)

where n₀(λ) is the refractive index of the tissue without glucose, k(λ)is the refractive index sensitivity to glucose concentration, and C isthe blood glucose concentration. Applying the relationship of equation(2), for a given radiation of wavelength λ, the correlation between thenumber (or frequency) N(C) of registered pulse circulations and theglucose concentration C can be expressed as:

$\begin{matrix}{{{N(C)} = \frac{t}{\frac{L \cdot \left( {{n_{0}(\lambda)} + {{k(\lambda)}*C}} \right)}{c} + {\Delta \; \tau}}};} & (3)\end{matrix}$

and as a corollary, the relationship between the changes in thefrequency of registered pulse circulations to glucose concentrationbecomes:

$\begin{matrix}\begin{matrix}{{\Delta \; {N(C)}} = {{{N(0)} - {N(C)}} =}} \\{= \frac{L \cdot {k(\lambda)} \cdot C \cdot t \cdot c}{\begin{matrix}{\left\lbrack {{L \cdot \left( {{n_{0}(\lambda)} + {{k(\lambda)} \cdot C}} \right)} + {\Delta \; {\tau \cdot c}}} \right\rbrack \cdot} \\\left\lbrack {{L \cdot {n_{0}(\lambda)}} + {\Delta \; {\tau \cdot c}}} \right\rbrack\end{matrix}}} \\{{\approx \frac{L \cdot {k(\lambda)} \cdot C \cdot t \cdot c}{\left\lbrack {{L \cdot {n_{0}(\lambda)}} + {\Delta \; {\tau \cdot c}}} \right\rbrack^{2}}};}\end{matrix} & (4)\end{matrix}$

where N(0) is the frequency of the pulse circulation when the glucoseconcentration C=0. As is apparent, by monitoring the changes in thepulse circulation frequency (PCF), the invention enables detection ofextremely small fluctuations in the glucose concentration within thetissue. The sensitivity S(C) of the device to the glucose concentrationcan be expressed as:

$\begin{matrix}{{S(C)} = {\frac{\left( {\Delta \; {N(C)}} \right)}{C} \cong {\frac{L \cdot {k(\lambda)} \cdot t \cdot c}{\left\lbrack {{L \cdot {n_{0}(\lambda)}} + {\Delta \; {\tau \cdot c}}} \right\rbrack^{2}}.}}} & (5)\end{matrix}$

Analysis of equation (5) shows that the glucose monitoring devicesensitivity is directly proportional to the measurement time interval tand inversely proportional to the EPU time delay, Δτ. The sensitivity isindependent of the glucose concentration level in the tissue, which isconsistent with the linear nature of the relationship between glucosemonitor output signal (pulse circulation frequency) and the glucoseconcentration level. In order not to saturate the measurement process,the optical pulse duration should be smaller (shorter) than EPU timedelay, Δτ.

A simulation of a glucose monitoring device employing radiation with awavelength of 850 nm in measuring glucose levels in a tissue withthickness L of 0.05 m was conducted to illustrate the relationshipbetween the output signal and glucose concentration and the effects ofthe EPU time delay. Measurement time interval t contained t=1 sec. At awavelength λ of 850 nm, for equation (2), the refractive indexsensitivity to the glucose concentration, k(λ)=1.515*10⁻⁶ (dL/mg) andn₀(λ)=1.325. (See, J. S. Maier, et. al. “Possible Correlation betweenBlood Glucose Concentration and Reduced Scattering Coefficient ofTissues in the Near-Infrared,” Optics Letters, Vol. 19, No. 24. pp.2062-2064, Dec. 15, 1994.) FIG. 2 is a graph depicting the change inpulse circulation frequency (that is, the output pulse circulationfrequency ΔN(C)) as a function of glucose concentration in the tissuewhen measured at three different EPU delay times of 1, 2, and 5nanoseconds. As is apparent, the pulse circulation frequency ΔN(C) has alinear relationship with the blood glucose level. The linear characterof the output signal (pulse circulation frequency) and the device'sability to exhibit constant sensitivity throughout the measurement rangeare important design criteria. Moreover, given that the glucoseconcentration is reflected in the changes of the pulse circulationfrequency, it is not necessary to calibrate the device against theglucose measurement range for an individual.

A simulation of a glucose monitoring device employing radiation with awavelength of 850 nm for measuring glucose levels in a tissue with athickness L of 0.05 m was conducted to illustrate the effects of themeasurement time interval. FIG. 3 is a graph of the glucose monitoringsensitivity as a function of EPU delay time as measured at threedifferent measurement time intervals of 1, 3, and 10 seconds. The datashows that using longer measurement time intervals increases thesensitivity and resolution. As is apparent from the graph, the inventiveglucose monitoring technique exhibits extremely high sensitivity andthus is capable of very accurate real time blood glucose levelmeasurements. The sensitivity data also demonstrate that the inventiveglucose monitoring device is capable of extremely high resolution. Forexample, when a device is operated at a 1 second measurement durationtime, a pulse circulation frequency of 10⁸ Hz (which corresponds to anEPU delay time of about 10⁻⁸ s), and an assumed counter frequency errorof about 10⁻¹ Hz, the glucose monitoring device is expected to exhibit aresolution of about 0.05 mg/dL.

With regard to sensitivity, a device reaches its theoretical limit whenΔτ=0:

$\begin{matrix}{{S(C)} \cong {\frac{{k(\lambda)} \cdot t \cdot c}{L \cdot {n_{0}^{2}(\lambda)}}.}} & (6)\end{matrix}$

Thus, for example, when a glucose monitoring device that is operating ata wavelength λ of 850 nm so that the refractive index sensitivity to theglucose concentration k(λ)=1.515*10⁻⁶ (dL/mg) and n₀(λ)=1.325 is used tomonitor tissue with a thickness L of 0.05 m, and c=3*10⁸ m/s, thetheoretical limit of the device sensitivity contains S_(th)(C)=4.5*10³Hz/(mg/dL) when the measurement time interval t is 1 second. Pulseduration is the limiting factor in this case.

FIG. 4 illustrates another embodiment of the glucose monitoring devicein which blood glucose levels are monitored in the time intervalmeasurement mode (also referred to as time measurement mode), whichmeans that the time interval necessary for the circulation of a definednumber of pulses is the measure of the glucose level. As shown, thisglucose monitoring device includes an optical or light source ofelectromagnetic radiation 11 and detector 12 which are connected toelectronic processing unit (EPU) 13. EPU 13, which includes anelectrical pulse generator 15, amplifier 16, counter 17 and timer 18, iscapable of generating, amplifying and counting electronic pulses andmonitoring time precisely. Source 11 and detector 12 are preferablydisposed on opposite sides of glucose-containing tissue 14, which is tobe monitored.

In operation, tissue 14 is positioned between source 11 and detector 12such that the thickness of the tissue through which radiation passesremains relatively constant during the monitoring process. Once tissue14 is secured, the device is activated so that pulse generator 15produces an initial single electrical pulse to optical source 11, inaddition, pulse generator 15 signals timer 18 to begin its timingmechanism. Upon receiving the single electrical pulse, optical source 11generates an optical pulse, which propagates through the monitoredtissue 14. When the optical pulse reaches detector 12, the detectorgenerates an electrical pulse to amplifier 16 which in turn commandscounter 17 to register a pulse circulation and signals pulse generator15 to generate another single electrical pulse. Thereupon, pulsegenerator 15 immediately generates a second single pulse to opticalsource 11 and the process of registering the circulating pulses isrepeated. When the number of registered pulse circulations reaches apre-selected and installed number, counter 17 sends a command to timer18 to record this time. In the meantime, pulse generator 5 continues togenerate pulses for a new measurement sequence. As further describedherein, for this technique, the time interval for the circulation of N₀pulses is proportional to the glucose concentration in the tissue and bygauging the changes in the time interval, fluctuations in theindividual's glucose concentration can be measured.

The dependence of the time interval t on the glucose concentration inthe tissue can be presented as:

$\begin{matrix}{{t(C)} = {N_{0} \cdot \left\lbrack {\frac{L \cdot \left( {{n_{0}(\lambda)} + {{k(\lambda)} \cdot C}} \right)}{c} + {\Delta \; \tau}} \right\rbrack}} & (7)\end{matrix}$

where, as before, L is the thickness of the monitored tissue, n₀(λ) isthe refractive index of the tissue without glucose, k(λ) is therefractive index sensitivity to glucose concentration, C is the bloodglucose concentration, c is the speed of light in vacuum, and Δτ is thetime delay in the EPU.

The relationship between the changes in the time of circulation of N₀pulses to blood glucose concentration can be expressed as:

$\begin{matrix}\begin{matrix}{{\Delta \; {t(C)}} = {{{t(C)} - {t(0)}} =}} \\{= {{N_{0} \cdot \left\lbrack {\frac{L \cdot \left( {{n_{0}(\lambda)} + {{k(\lambda)} \cdot C}} \right)}{c} + {\Delta \; \tau}} \right\rbrack} -}} \\{{N_{0} \cdot \left\lbrack {\frac{L \cdot {n_{0}(\lambda)}}{c} + {\Delta \; \tau}} \right\rbrack}} \\{= {\frac{N_{0} \cdot L \cdot {k(\lambda)}}{c} \cdot {C.}}}\end{matrix} & (8)\end{matrix}$

where t(0) is the time interval required to achieve N₀ pulses ofcirculation when glucose concentration C=0.

Finally, the sensitivity S(C) of the device operating in the timemeasurement mode to the glucose concentration can be expressed as:

$\begin{matrix}{{S(C)} = {\frac{\left( {\Delta \; {N(C)}} \right)}{C} = {\frac{N_{0} \cdot L \cdot {k(\lambda)}}{c}.}}} & (9)\end{matrix}$

As is apparent, the device sensitivity in the time measurement mode isdirectly proportional to the number of pulse circulation N₀, tissuethickness L and the refractive index sensitivity to glucoseconcentration k(λ), and does not depend on the EPU time delay Δτ andtissue refractive index n₀(λ) without presence of glucose. It isexpected that the glucose monitoring device operating in the timemeasurement mode will have comparable accuracy and sensitivity as thatof the glucose monitoring device configured to operate in the pulsemeasurement mode as shown in FIG. 1.

The glucose monitoring devices of the present invention can employ acombination of measurements at different wavelengths to compensate forvariations in tissue thickness and its temperature, and presence ofother blood components during glucose monitoring, and other factors. Inthis case, the system can employ a single broadband source withappropriate band pass filters and a detector that is capable ofdetecting radiation at different wavelengths. Alternatively, the systemcan employ a plurality measurement channels with each channel preferablyhaving a light source and receiver or detector. In either case, thesystem can use one or several EPUs. The data that is gather either inthe pulse measurement mode or the time measurement mode.

Because both channels are subject to the same major sources of error,e.g., background changes, the combination of data will provide a highlyaccurate indication of the amount of glucose present.

In addition to measuring glucose, the device can also be designed tomonitor other analytes by selected the appropriate wavelength for themeasurement source and detector. These analytes include, for example,cholesterol, triglycerides, urea, amino acids, and proteins, e.g.,albumin and enzymes. Moreover, the device can be designed to measure aplurality of analytes simultaneously by employing radiation with aplurality of different wavelength regions that are responsive to theanalytes being monitor.

FIG. 5 illustrates another embodiment of the glucose monitoring devicethat includes two separate EPUs and associated optical sources anddetectors to monitor tissue 50. EPU 52 operates optical source 56 thatgenerates a reference radiation and detector 54 and EPU 58 operatesoptical source 60 that generates a measurement radiation and detector62. Both EPUs preferably operate in the same measurement mode, i.e.,time measurement mode or pulse measurement mode. Alternatively, one canoperate in the time measurement mode and the other in the pulsemeasurement mode. Analysis of the combined readings provides an accuratemeasurement of the glucose concentration of tissue 50 as describedabove.

Implementing the two EPU design illustrated in FIG. 5 is complicated inthat constructing two identical electronic processing units is oftendifficult to achieve. Each EPU may have different technical parametersand sensitivities to environmental factors such as temperature orhumidity that affect the accuracy and repeatability of the measurement.

FIG. 6 illustrates a glucose level monitoring unit that obviates thisproblem by employing a single EPU 103 that controls measurements alongall the measurement channels which will improve accuracy andrepeatability of the monitoring. EPU 103 includes multiplexer 109 alongwith processor 110, counter 107, pulse generator 105, timer 108, andamplifier 106. The device is configured to have two measurement channelsthrough tissue 124: (i) the first is defined by the arrangement ofoptical source 126 and detector 121 and (ii) the second by thearrangement of optical source 126 and detector 122. Optical source 126can be a single broadband source or one that contains several individualsources emitting at a different wavelengths. To avoid interference withother measurement channels, each detector 121 and 122 can be equippedwith an optical filter to monitor radiation at the desired wavelength.The device can be designed to operate in the pulse measurement modeand/or time measurement mode.

FIG. 7 illustrates an arrangement of the optical sources and detectorsthat includes a plurality individual optical sources and detectors. Inthis embodiment, optical source 80, which consists of three individualoptical sources, emits radiation at three distinct wavelengths that aredetected by three corresponding detectors each equipped with anindividual optical filter that selectively transmits radiation within aparticular wavelength range. So that radiation propagates throughessentially the same monitored area of tissue or has the same physicalpath for different measurement channels, the individual optical sourcesshould be positioned close to each other and similarly the individualdetectors should be arranged in close proximity as well.

A technique for ensuring that radiation of different wavelengthspropagates through the monitored tissue along the same physical pathuses optical combining and optical splitting which are illustrated inFIGS. 8A and 8B. An optical combiner 84 combines signals from aplurality of optical sources; in this case, three optical sources 85, 86and 87, which emit radiation having wavelengths of λ1, λ2, and λ3,respectively. In the configuration shown in FIG. 8A, detector 88, withthree corresponding detectors, is positioned on the opposite side of thetissue to receive the signals. In the configuration shown in FIG. 8B, anoptical splitter 90 delivers input radiation to the detectors 91, 92,and 93, which detect radiation at wavelengths of λ1, λ2, and λ3,respectively.

In operation of the glucose monitoring device of FIG. 6, on command fromprocessor 110, multiplexer 109 connects detector 121 to the input ofamplifier 106. The blood glucose concentration is measured by operationof the first measurement channel that includes source 126 and detector121 at wavelength λ1. In the same fashion, on command from processor110, multiplexer 109 connects detector 122 to the input of amplifier106. The blood glucose concentration is then measured via the secondmeasurement channel that includes source 126 and detector 122 atwavelength λ2. Processor 110 calculates glucose concentration levelbased on both measurements. With this device, employing the sameelectronic components in the single EPU 103 during all phases ofmeasurements decreases electronics instability error. At the same time,obtaining 2-wavelength measurements provide temperature sensitivitycompensation that improves the accuracy of the glucose monitoring. As isapparent, the total number of measurement channels and correspondingwavelengths can be more than 2 if desired.

FIG. 9 illustrates another embodiment of the glucose monitoring devicewith multiple measurement channels that employs a single EPU 163 thatincludes demultiplexer 153, processor 160, counter 157, pulse generator155, timer 158, and amplifier 156. The device is equipped with dualoptical sources 161, 162 that emit radiation at two distinct wavelengthsλ1 and λ2, respectively, and a single detector 165 which is capable ofdetecting radiation at both wavelengths. The device is configured toform two measurement channels: (i) the first is defined by thearrangement of optical source 161 and detector 165 and (ii) the secondby the arrangement of optical source 162 and detector 165.

On command from processor 160, demultiplexer 153 connects pulsegenerator 155 with source 161. In this configuration, the blood glucoseconcentration calculated through measurements from the first measurementchannel at wavelength λ1. Similarly, on command from processor 150,demultiplexer 153 connects pulse generator 155 to source 162 whereby theblood glucose concentration is calculated based on measurements from thesecond measurement channel at wavelength λ2.

As is apparent, the number of optical sources and correspondingmeasurement channels (and wavelengths) employed with this device can begreater than two, if desired. The device can operate in both modes:pulse measurement mode and time measurement mode. In order for theradiation to propagate through the same monitored area of tissue 164 orto have the same physical path for different measurement channels, theoptical sources should positioned close to each other. Optical combiningand splitting can be also used to ensure the same physical pass of thepropagating through the monitored tissue radiation of the differentwavelengths.

Attenuation of the propagating radiation is a very good indicator ofenvironmental conditions within tissue, thus besides measuring therefractive index of tissue, the glucose monitoring device measures theattenuation of radiation that is propagated through tissue. Bymonitoring the coefficient of attenuation it is possible, for example,to compensate for temperature variations. In general, monitoring thecoefficient of attenuation improves the glucose concentrationmeasurements by compensating for background variations.

FIG. 10 illustrates a glucose level monitoring device configured tomeasure both refractive index and attenuation that employs a single EPU133 that includes multiplexer 139 along with processor 150, counter 137,pulse generator 135, timer 138, and amplifier 136. This device isequipped with a first detector 141 and a second detector 142 arranged todefine two measurement channels: (i) the first is defined by thearrangement of optical source 146 and detector 141 and (ii) the secondby the arrangement of optical source 146 and detector 142. The firstdetector 141 is positioned directly opposite optical source 146 at adistance L1. The second detector 142 is positioned laterally from firstdetector 141 at a distance S so that the distance between optical source146 and detector 142 is L2, where L₂=(L₁ ²+S²)^(0.5). In operation,multiplexer 139 commutates the two detectors' output signals toprocessor 150 and to amplifier 136 at the same time. The attenuationcoefficient can be calculated from the signals from detector 141 and 142which are derived from radiation traveling from optical source 146through tissue 144 along paths L₁ and L₂, respectively.

FIG. 11 illustrates another embodiment of a multiple measurement channelglucose monitoring device that employs a single EPU 183 that includeselectronic multiplexer 179, electronic demultiplexer 173, processor 170,counter 177, pulse generator 175, timer 178, and amplifier 176. Thedevice is equipped with optical sources 181 and 182 that emit radiationat two distinct wavelengths λ1 and λ2, respectively, that are detectedby corresponding detectors 185 and 186, respectively. To prevent theinfluence of scattered radiation from the adjacent measurement path,each detector is equipped with the appropriate optical filter thattransmits radiation in the selected wavelength range. The device isconfigured to form two measurement channels: (i) the first is defined bythe arrangement of optical source 181 and detector 185 and (ii) thesecond by the arrangement of optical source 182 and detector 186. Theoutput from detectors 185 and 186 are connected to the input ofmultiplexer 179 and the output from multiplexer 179 is an input toamplifier 176. Pulse generator 175 is connected to the input ofdemultiplexer 173, while demultiplexer outputs are connected to sources181 and 182. As is apparent, the number of measurement channels andwavelengths employed can be more than two if desired.

In operation, on command from processor 170, demultiplexer 173 connectspulse generator 175 with source 181 and multiplexer 179 connectsdetector 185 to the input of amplifier 176. In this configuration, theblood glucose concentration in tissue 180 is calculated based on a datafrom the first measurement channel. Similarly, on command from processor170, demultiplexer 173 connects pulse generator 175 to optical source182 and multiplexer 179 connects detector 186 to the input of amplifier176. In this configuration the blood glucose concentration is calculatedbased on a data from the second measurement channel. The device canoperate in the pulse measurement mode and/or time measurement mode.

Another technique for improving the accuracy of glucose measurements isto account for tissue background conditions. This can be accomplishedwith the glucose monitoring device shown in FIG. 12, which measuresforward and back scattering radiation along with the intensity of thetransmitted optical pulses through tissue 254. The device employs asingle EPU 233 that includes processor 240, counter 247, pulse generator245, timer 248, amplifiers 206, 246 and 249. An optical source 251 andprimary detector 255 are arranged to define a primary measurementchannel. In operation, processor 240 monitors the amplitude of theoptical pulses by monitoring the output of amplifier 246, whereas firstand second secondary detectors 253 and 252 are positioned to monitor theintensities of the forward and back scattering radiation, respectively,that are generated as the optical pulses propagate from optical source251 to primary detector 255.

The blood glucose concentration is calculated on the basis of themeasured optical pulse frequency circulation and its intensity and theintensities of the forward and/or back scattering radiation. The samefunctionality is applicable to the time measurement mode.

The same scattering radiation technique can be applied to eachmeasurement channel in a glucose concentration monitoring device thathas multiple measurement channels. For example, as shown in FIG. 13,this 2-channel 2-wavelength design includes means for measuring forwardand back scattering associated with each of the primary two primarymeasurement channels.

As shown, the glucose monitoring device employs a single EPU 263 thatincludes electronic multiplexer 289, electronic demultiplexer 281,processor 270, counter 277, pulse generator 275, timer 285, andamplifier 286. The device is equipped with optical sources 292 and 293that emit radiation at two distinct wavelengths λ1 and λ2, respectively,that are detected by corresponding detectors 297 and 298, respectively.To prevent the influence of scattered radiation from the adjacentmeasurement path, each detector with the appropriate an optical filterthat transmits radiation the selected wavelength range. The output fromdetectors 297 and 298 are connected to the input of multiplexer 289 andthe outputs from multiplexer 289 are inputs to amplifier 286. Pulsegenerator 275 is connected to the input of demultiplexer 281, whiledemultiplexer outputs are connected to sources 292 and 293.

The device is further equipped with first and second secondary detectors296 and 291 which are positioned to detect the intensities of theforward and back scattering, respectively, that is generated asradiation with a wavelength of λ1 from optical source 292 propagatesthrough tissue 294. Similarly, third and fourth secondary detectors 299and 295 are positioned to detect the intensities of the forward and backscattering, respectively, generated by radiation with a wavelength of λ2from optical source 293. Preferably, secondary detectors 291 and 296have transmission filters at λ1, and detectors 295 and 299 havetransmission filters at λ2. Signals from detectors 291, 295, 296 and299, prior to being amplified, are delivered to process 270 in the samemanner as presented in FIG. 12.

In operation, on command from processor 270, demultiplexer 281 connectspulse generator 275 with source 292 and multiplexer 289 connectsdetector 297 to the input of amplifier 286. In this configuration, theblood glucose concentration is calculated from measurements derived fromthis first measurement channel. Similarly, on command from processor270, demultiplexer 281 connects pulse generator 275 to optical source293 and multiplexer 298 connects detector 298 to the input of amplifier286. In this configuration the blood glucose concentration is calculatedfrom measurements derived from the measurement channel. The device canoperate in the pulse measurement mode and/or time measurement mode atboth wavelengths.

The blood glucose concentration is calculated on the basis of themeasured optical pulse frequency circulation and its intensity and theintensities of the forward and/or back scattering radiation. The samefunctionality is applicable to the time measurement mode.

The glucose monitoring device can be employed to monitor tissue from anypart of an individual, which allows the propagation of the opticalpulse. A preferred device as shown in FIG. 14 is designed to be wornaround the wrist. The device includes an EPU 34 and associated opticalsource 36 and detector 32. The EPU 34 and detector 32 are enshrouded ina protective case or housing 30 while optical source 36 is attached toan adjustable wristband 40. Wrist band 40 is worn so that detector 32and optical source 36 are preferably on direct opposite sides of thewrist so that radiation emitted from optical source 36 is received bydetector 32 after passing through the tissue. Optical source 36 isconnected to EPU 34 via cable 38 that is embedded in wristband 40. Asshown in FIGS. 15 and 16, the glucose monitor device can also include aliquid crystal display unit 42 with a glucose indicator on the face ofcase surface 36. The display unit can also comprise a printer, a displayscreen, or a magnetic or optical recording device.

For individuals who have serious diabetic conditions, the display unitcan include a control apparatus that regulates an insulin pump orsimilar infusion device that is worn or implanted on the individual'sbody. When configured to be surgically implanted into a user, forexample, at a particular location in the venous system, along the spinalcolumn, in the peritoneal cavity, or other suitable site to deliver aninfusion formulation to the user. External infusion pumps, which connectto patients through suitable catheters or similar devices, can also beemployed. Implantable devices that supply insulin are described, forexample, in U.S. Pat. No. 6,122,536 to Sun et al. and US PatentPublication No. 2004/0204673 to Flaherty, U.S. Pat. No. 7,024,245 toLebel et al, U.S. Pat. No. 6,827,702 to Lebel et al., U.S. Pat. No.6,427,088 to Bowman et al., and U.S. Pat. No. 5,741,211 to Renirie etal., which are incorporated herein by reference.

As shown in FIG. 17, an insulin pump 20 responds to signals transmittedfrom a glucose monitoring device 22 to control the administration ofinsulin. For example, the glucose monitoring device can be equipped witha control circuit that generates a control signal, such as a radiofrequency (RF) signal, for remotely controlling the insulin pump 20which is equipped with an antenna to receive the control signals. Thecontrol signals are converted to actuator signals that regulate anactuator driver within the insulin pump 20. Should the measured glucoselevel of the individual fall below a prescribed threshold, the glucosemonitoring device can signal the insulin pump to deliver an appropriateamount of a medical formulation such as an insulin formulation into theindividual. The insulin pump 20 can be equipped with an actuator driverthat is responsive to the actuator signals and thereby inject an amountof insulin formulation from a reservoir within the insulin pump and intothe individual. In addition, glucose monitoring device 22 can transmitsignals to a database 24 and doctor's office 26 with a record of theglucose levels.

For convenience of use, as shown in FIGS. 18A and 18B, the glucosemonitoring device 95 is housed in an earpiece that is worn on apatient's ear. The device includes optical sources 96 and detectors 97that are positioned opposite sides of an earlobe, which is heavilysaturated with blood vessels. Measurements can be transmitted to theblood glucose level display, which can be worn on the patient's wrist.As depicted in FIG. 17, the glucose monitoring device can generates acontrol signal for remotely controlling the insulin pump 20 or transmitsignals to a database 24 and doctor's office 26 with a record of theglucose levels.

The foregoing has described the principles, preferred embodiments andmodes of operation of the present invention. However, the inventionshould not be construed as limited to the particular embodimentsdiscussed. Instead, the above-described embodiments should be regardedas illustrative rather than restrictive, and it should be appreciatedthat variations may be made in those embodiments by workers skilled inthe art without departing from the scope of present invention as definedby the following claims.

1. A device for noninvasive measurement of the levels of at least oneanalyte in a subject that comprises: means for irradiating the subjectthrough tissue with electromagnetic radiation; means for detecting theradiation that passes through the tissue; means for calculating thespeed at which the electromagnetic radiation passes through the tissue;means for monitoring at least one of back or forward scattering ofelectromagnetic radiation within the tissue; and means for correlatingthe calculated speed of the electromagnetic radiation to theconcentration of the at least one analyte in the subject.
 2. The deviceof claim 1 comprising mean for monitoring of attenuation ofelectromagnetic radiation within the tissue
 3. The device of claim 1comprising means for monitoring both back and forward scatting ofelectromagnetic radiation within the tissue.
 4. The device of claim 1wherein the means for irradiating the subject emits pulses of radiationand the means for detecting the radiation measures the number of pulsesof radiation that passes through the tissue during a defined time periodwhich is referred as the pulse circulation frequency measurement.
 5. Thedevice of claim 4 wherein means for correlating the calculated speed ofthe electromagnetic radiation to the concentration of the at least oneanalyte in the subject calculates the changes, if any, of the pulsecirculation frequency being measured.
 6. The device of claim 1 whereinthe means for irradiating the subject emits pulses of radiation and themeans for detecting the radiation measures the time period required fora defined number of pulses of radiation to pass through the tissue whichis referred to as the time interval measurement.
 7. The device of claim6 wherein means for correlating the calculated speed of theelectromagnetic radiation to the concentration of the at least oneanalyte in the subject calculates the changes, if any, of the timeinterval being measured.
 8. The device of claim 1 further comprisingmeans for dispensing a medical formulation in response to adetermination of the concentration of the at least one analyte in thesubject.
 9. The device of claim 1 wherein the at least one analyte isselected from the group consisting of glucose, cholesterol,triglycerides, urea, protein, and mixtures thereof.
 10. The device ofclaim 1 wherein said at least one analyte is glucose.
 11. The device ofclaim 1 wherein the concentration of two or more analytes are measuredand the means for irradiating the subject emits electromagneticradiation at two or more different wavelengths.
 12. The device of claim1 wherein the means for irradiating the subject through tissue withelectromagnetic radiation at different wavelengths in order tocompensate for variations in conditions other than the concentration ofthe analyte or analytes being measured.
 13. The device of claim 1wherein the means for irradiating the subject comprises means forsupporting the device such that the electromagnetic radiation passesthrough a defined thickness of the tissue.
 14. A device for noninvasivemeasurement of the levels of at least one analyte in a subject thatcomprises: means for irradiating the subject through tissue withelectromagnetic radiation; means for detecting the radiation that passesthrough the tissue; means for calculating the speed at which theelectromagnetic radiation passes through the tissue; and means forcorrelating the calculated speed of the electromagnetic radiation to theconcentration of the at least one analyte in the subject, wherein thedevice defines a plurality of measuring channels and wherein theplurality of measuring channels are operated by a single electronicprocessing unit.
 15. The device of claim 14 comprising a plurality ofoptical sources of electromagnetic radiation that irradiates the tissue.16. The device of claim 14 comprising a plurality of detectors thatdetect radiation that is transmitted through the tissue.
 17. The deviceof claim 14 wherein the electronic processing unit comprises amultiplexer and a demultiplexer.
 18. The device of claim 14 comprisingan optical combiner that combines signals from a plurality of opticalsources and an optical splitter that delivers input radiation to aplurality of detectors.
 19. The device of claim 14 wherein themeasurement channels have physical paths of different lengths
 20. Thedevice of claim 14 comprises means for monitoring at least one of backor forward scattering radiation.
 21. The device of claim 20 thatcomprises means for monitoring both of back and forward scatteringradiation.
 22. A device for noninvasive measurement of the levels ofglucose in a subject that comprises: means for irradiating the subjectthrough tissue with electromagnetic radiation having a wavelength suchthat the speed of the electromagnetic radiation propagating through thetissue is sensitive to the glucose concentration in the tissue; meansfor detecting the radiation that passes through the tissue; means forcalculating the speed at which the electromagnetic radiation passesthrough the tissue; means for monitoring at least one of back or forwardscattering of electromagnetic radiation within the tissue; and means forcorrelating the calculated speed of the electromagnetic radiation to theconcentration of glucose in the subject.
 23. The device of claim 22comprising means for monitoring of attenuation of electromagneticradiation within the tissue.
 24. The device of claim 22 wherein themeans for irradiating the subject emits pulses of radiation and themeans for detecting the radiation measures the number of pulses ofradiation that passes through the tissue during a defined time period,which is referred as the pulse circulation frequency measurement. 25.The device of claim 24 wherein the means for correlating the calculatedspeed of the electromagnetic radiation to the concentration of theglucose in the subject calculates the changes, if any, of the pulsecirculation frequency being measured.
 26. The device of claim 22 whereinthe means for irradiating the subject emits pulses of radiation and themeans for detecting the radiation measures the time period required fora defined number of pulses of radiation to pass through the tissue whichis referred to as the time interval measurement.
 27. The device of claim26 wherein the means for correlating the calculated speed of theelectromagnetic radiation to the concentration of the at least oneanalyte in the subject calculates the changes, if any, of the timeinterval being measured.
 28. The device of claim 22 further comprisingmeans for dispensing an insulin formulation in response to adetermination of the concentration of the glucose in the subject.
 29. Adevice for noninvasive measurement of the levels of glucose in a subjectthat comprises: means for irradiating the subject through tissue withelectromagnetic radiation having a wavelength such that the speed of theelectromagnetic radiation propagating through the tissue is sensitive tothe glucose concentration in the tissue; means for detecting theradiation that passes through the tissue; means for calculating thespeed at which the electromagnetic radiation passes through the tissue;and means for correlating the calculated speed of the electromagneticradiation to the concentration of glucose in the subject, wherein thedevice defines a plurality of measuring channels and wherein theplurality of measuring channels are operated by a single electronicprocessing unit.
 30. The device of claim 29 comprising a plurality ofoptical sources of electromagnetic radiation that irradiates the tissue.31. The device of claim 29 comprising a plurality of detectors thatdetect radiation that is transmitted through the tissue.
 32. The deviceof claim 29 wherein the electronic processing unit comprises amultiplexer and a demultiplexer.
 33. The device of claim 29 comprisingan optical combiner that combines signals from a plurality of opticalsources and an optical splitter that delivers input radiation into aplurality of detectors.
 34. The device of claim 29 wherein themeasurement channels have physical paths of different lengths.
 35. Thedevice of claim 29 comprises means for monitoring at least one offorward or back scattering radiation.
 36. The device of claim 35 thatcomprises means for monitoring both of forward and back scatteringradiation.
 37. A noninvasive method of monitoring the levels of at leastone analyte in a subject that comprises: (a) irradiating the subjectthrough tissue of known thickness with electromagnetic radiation; (b)detecting the radiation that passes through the tissue; (c) calculatingthe speed at which the electromagnetic radiation passed through thetissue; and (d) correlating the calculated speed of the electromagneticradiation to the concentration of the at least one analyte in thesubject.
 38. The method of claim 37 that further comprises monitoringattenuation of the radiation that passes through the tissue.
 39. Themethod of claim 37 that further comprises monitoring at least one ofback or forward scattering of electromagnetic radiation within thetissue.
 40. The method of claim 37 that further comprises monitoring ofboth back and forward scattering of electromagnetic radiation within thetissue.
 41. The method of claim 37 wherein step (a) comprises ofdirecting pulses of radiation through the tissue and step (b) comprisesof detecting the pulses that passes through the tissue during a definedtime period, which is referred as the pulse circulation frequencymeasurement.
 42. The method of claim 41 wherein step (d) comprises ofcalculating the changes, if any, of the pulse circulation frequencybeing measured.
 43. The method of claim 37 wherein step (a) comprises ofdirecting pulses of radiation and step (b) comprises of measuring thetime period required for a defined number of pulses of radiation to passthrough the tissue which is referred to as the time intervalmeasurement.
 44. The method of claim 43 wherein step (d) comprise ofcalculating the changes, if any, of the time interval being measured.45. The method of claim 37 further comprising the step of dispensing amedical formulation in response to a determination of the concentrationof the at least one analyte in the subject.
 46. The method of claim 37wherein the at least one analyte is selected from the group consistingof glucose, cholesterol, triglycerides, urea, protein, and mixturesthereof.
 47. The method of claim 37 wherein said at least one analyte isglucose.
 48. The method of claim 37 wherein the concentration of two ormore analytes are measured and step (a) comprises of irradiating thesubject with electromagnetic radiation at two or more differentwavelengths.
 49. The method of claim 37 wherein step (a) comprises ofirradiating the subject through tissue with electromagnetic radiation atdifferent wavelengths in order to compensate for variations inconditions other than the concentration of the analyte or analytes beingmeasured.